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The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.

Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L - Mol. Syst. Biol. (2012)

Bottom Line: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density.A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response.Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.

ABSTRACT
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

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Modeling the impact of inoculum effect (IE) on periodic antibiotic treatment. (A) A simplified model that describes population dynamics in periodic pulses of an antibiotic. Cases (i) and (ii) cause the same dynamics as indicated by the top panel. Case (iii) causes the dynamics as indicated by the bottom panel. See Supplementary Figure S6A for functions of τlag. (B) IE is predicted to cause band-pass response of bacterial growth to periodic treatment (bottom panel). Without IE, bacterial density increased with increasing pulse periods (top panel). μ1=μ2=0.07, N0=10−6, Nc=10−5, and Nmax=10−3. Each line corresponds to a specific pulse period (T) as indicated next to the line. Note that in the bottom panel (with IE), time series of both T=500 and T=10 min are identical. (C) With IE, the effective growth duration (T/2−τlag) in each cycle first increases and then decreases with T, leading to band-pass bacterial response. Without IE, the effective growth duration increases monotonically with T. See Supplementary Figure S6 for additional data.
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f6: Modeling the impact of inoculum effect (IE) on periodic antibiotic treatment. (A) A simplified model that describes population dynamics in periodic pulses of an antibiotic. Cases (i) and (ii) cause the same dynamics as indicated by the top panel. Case (iii) causes the dynamics as indicated by the bottom panel. See Supplementary Figure S6A for functions of τlag. (B) IE is predicted to cause band-pass response of bacterial growth to periodic treatment (bottom panel). Without IE, bacterial density increased with increasing pulse periods (top panel). μ1=μ2=0.07, N0=10−6, Nc=10−5, and Nmax=10−3. Each line corresponds to a specific pulse period (T) as indicated next to the line. Note that in the bottom panel (with IE), time series of both T=500 and T=10 min are identical. (C) With IE, the effective growth duration (T/2−τlag) in each cycle first increases and then decreases with T, leading to band-pass bacterial response. Without IE, the effective growth duration increases monotonically with T. See Supplementary Figure S6 for additional data.

Mentions: To address this question, we constructed a population-based simple model that incorporates two essential features of our experimental observations: IE and its impact on recovery time (Figure 6A). Without IE, bacterial populations grow at rate μ2 after a lag time τlag without an antibiotic and do not grow with the antibiotic (Figure 6A, case i). Based on experimental measurements, we assumed that τlag increases exponentially with the duration of an antibiotic that exhibits IE and stays constant otherwise (Supplementary Figure S6A). With IE and N<Nc (which is a function of antibiotic concentration, Figure 1B and C), bacterial populations grow in the same way as the case above (Figure 6A, case ii). With IE and N>Nc, bacterial populations grow at rate μ2 without the antibiotic and at rate μ1 with the antibiotic (Figure 6A, case iii). We note that this model assumed that bacteria would not grow when antibiotic concentration is above a certain threshold and would recover with a time delay when antibiotic concentration decreases below a certain threshold. As such, the inclusion of antibiotic decay dynamics could reduce the effective time that an antibiotic inhibits bacterial growth.


The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.

Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L - Mol. Syst. Biol. (2012)

Modeling the impact of inoculum effect (IE) on periodic antibiotic treatment. (A) A simplified model that describes population dynamics in periodic pulses of an antibiotic. Cases (i) and (ii) cause the same dynamics as indicated by the top panel. Case (iii) causes the dynamics as indicated by the bottom panel. See Supplementary Figure S6A for functions of τlag. (B) IE is predicted to cause band-pass response of bacterial growth to periodic treatment (bottom panel). Without IE, bacterial density increased with increasing pulse periods (top panel). μ1=μ2=0.07, N0=10−6, Nc=10−5, and Nmax=10−3. Each line corresponds to a specific pulse period (T) as indicated next to the line. Note that in the bottom panel (with IE), time series of both T=500 and T=10 min are identical. (C) With IE, the effective growth duration (T/2−τlag) in each cycle first increases and then decreases with T, leading to band-pass bacterial response. Without IE, the effective growth duration increases monotonically with T. See Supplementary Figure S6 for additional data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472685&req=5

f6: Modeling the impact of inoculum effect (IE) on periodic antibiotic treatment. (A) A simplified model that describes population dynamics in periodic pulses of an antibiotic. Cases (i) and (ii) cause the same dynamics as indicated by the top panel. Case (iii) causes the dynamics as indicated by the bottom panel. See Supplementary Figure S6A for functions of τlag. (B) IE is predicted to cause band-pass response of bacterial growth to periodic treatment (bottom panel). Without IE, bacterial density increased with increasing pulse periods (top panel). μ1=μ2=0.07, N0=10−6, Nc=10−5, and Nmax=10−3. Each line corresponds to a specific pulse period (T) as indicated next to the line. Note that in the bottom panel (with IE), time series of both T=500 and T=10 min are identical. (C) With IE, the effective growth duration (T/2−τlag) in each cycle first increases and then decreases with T, leading to band-pass bacterial response. Without IE, the effective growth duration increases monotonically with T. See Supplementary Figure S6 for additional data.
Mentions: To address this question, we constructed a population-based simple model that incorporates two essential features of our experimental observations: IE and its impact on recovery time (Figure 6A). Without IE, bacterial populations grow at rate μ2 after a lag time τlag without an antibiotic and do not grow with the antibiotic (Figure 6A, case i). Based on experimental measurements, we assumed that τlag increases exponentially with the duration of an antibiotic that exhibits IE and stays constant otherwise (Supplementary Figure S6A). With IE and N<Nc (which is a function of antibiotic concentration, Figure 1B and C), bacterial populations grow in the same way as the case above (Figure 6A, case ii). With IE and N>Nc, bacterial populations grow at rate μ2 without the antibiotic and at rate μ1 with the antibiotic (Figure 6A, case iii). We note that this model assumed that bacteria would not grow when antibiotic concentration is above a certain threshold and would recover with a time delay when antibiotic concentration decreases below a certain threshold. As such, the inclusion of antibiotic decay dynamics could reduce the effective time that an antibiotic inhibits bacterial growth.

Bottom Line: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density.A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response.Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.

ABSTRACT
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

Show MeSH
Related in: MedlinePlus